The present invention relates to a process for producing paroxetine, which has an inhibitory action on 5-hydroxytryptamine (5-HT) and is useful as a therapeutic agent for various disease such as depression and Parkinson""s disease.
Paroxetine is (3S, 4R)-3-[5-(1,3-dioxaindanyl)oxymethyl]-4-(p-fluorophenyl)piperidine represented by the after-mentioned formula (4).
As processes for producing paroxetine, the process of Christensen et al. (U.S. Pat. No. 4,007,196) and the process of Barnes et al. (Japanese Examined Patent Publication JP-B-6-47587) have been known. The former comprises reacting a N-methylpiperidine derivative represented by the after-mentioned general formula (1) (wherein R1 is a methyl group) with phenyl chloroformate and hydrolyzing the resulting phenyl carbamate under alkaline conditions. The phenyl carbamate is different from compounds represented by the after-mentioned formula (3) only in that R2 is a phenyl group. This process has drawbacks attributed to the low degree of conversion into the phenyl carbamate, that extra time and labor are required to separate the starting materials from the product, and that the ultimate yield by the process is low.
The latter process comprises converting a N-methylpiperidine derivative represented by the general formula (1) to a 1-chloroethyl carbamate represented by the following formula (5) and then hydrolyzing the 1-chloroethyl carbamate under acidic conditions. This process requires heating or stirring for a long time under acidic conditions, which may cause decomposition of the acetal moiety of the product. Prevention of contamination of an end product by the decomposition by-product requires much labor and cost which are greatly disadvantageous to production of medicines. 
In order to solve the problems with the above-mentioned processes, the present invention provides: a process for producing paroxetine represented by the following formula (4), which comprises reacting an N-alkylpiperidine represented by the following general formula (1) with a haloformic acid ester represented by the general formula (3) to prepare an alkoxycarbonylpiperidine represented by the general formula (3), and hydrolyzing the alkoxycarbonylpiperidine under alkaline conditions: 
wherein each of R1 and R2 is a lower alkyl group, a lower cycloalkyl group, an aralkyl group or CmF2m+1 (wherein m is an integer of from 1 to 6), and X is a halogen atom.
Hereinabove and hereinafter, xe2x80x9clowerxe2x80x9d for an organic group means from 1 to 6 carbon atoms. Suitable examples of a xe2x80x9clower alkyl groupxe2x80x9d include a methyl group, an ethyl group, a propyl group, an isopropyl group, a butyl group, an isobutyl group, a t-butyl group, a pentyl group, a hexyl group and the like. A xe2x80x9clower cycloalkyl groupxe2x80x9d means a cycloalkyl group having from 3 to 6 carbon atoms on its ring, and its suitable examples include a cyclopropyl group, a cyclobutyl group, a cyclopentyl group and a cyclohexyl group.
An xe2x80x9caralkyl groupxe2x80x9d means an alkyl group substituted with an aryl group. An xe2x80x9caryl groupxe2x80x9d, means a monovalent aromatic hydrocarbon group or a monovalent heterocyclic group and is preferably a phenyl group or its derivative or an oxygen-, nitrogen- or sulfur-containing 5- or 6-membered ring or a condensed heterocyclic ring derived therefrom. Suitable examples of an aryl group include a phenyl group, a tolyl group, a p-halphenyl group, a thiophenyl group, a pyrrolyl group, an imidazolyl group, a pyridyl group and an indolyl group. The alkyl moiety of an aralkyl group preferably has a carbon number of 4 or less. Suitable examples of an aralkyl group are a benzyl group, a benzhydryl group, a trityl group and a phenethyl group.
A xe2x80x9chalogen atomxe2x80x9d means a fluorine atom, a chlorine atom, a bromine atom or an iodine atom. CmF2m+1 means a perfluoroalkyl group, and m is preferably 1 or 2.
An N-alkylpiperidine represented by the general formula (1) as the starting material for the process of the present invention is obtainable by the process disclosed in U.S. Pat. No. 4,007,197. A haloformic acid ester represented by the general formula (2) is readily commercially available and also can be synthesized by known methods.
In order to carry out the process of the present invention, firstly, an N-alkylpiperidine represented by the general formula (1) [hereinafter referred to as a compound (1)] together with a haloformic acid esters represented by the general formula (2) [hereinafter referred to as a compound (2)] is stirred in an appropriate solvent in the presence or absence of an appropriate base at an appropriate temperature to prepare an alkoxycarbonylpiperidine represented by the general formula (3) [hereinafter referred to as a compound (3)].
The N-alkyl group moiety (R1) of the compound (1) used here is preferably a lower alkyl group, more preferably a methyl group. The halogen atom (X) of the compound (2) used here is preferably a chlorine atom or a bromine atom, and particularly preferred is a chlorine atom. The alkyl moiety (R2) of the compound (2) is preferably a lower alkyl group, more preferably a methyl group or an ethyl group.
The reaction temperature is preferably from 10 to 150xc2x0 C., more preferably from 20 to 120xc2x0 C. The amount of a compound (2) is preferably at least equivalent to, more preferably 1 to 10 times as many equivalents as the amount of the compound (1). The reaction is preferably carried out in the presence of a base so as to proceed satisfactorily.
Any aprotic solvents except for amines may be used in the above reaction, and when a base is present, a solvent resistant to the base is preferred. Suitable examples of the solvent are dichloromethane, chloroform, diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, hexane, heptane, petroleum ether, methyl acetate, ethyl acetate, N,N-dimethylformamide and N,N-dimethylacetamide. Among them, aromatic solvents such as toluene and ethereal solvents such as tetrahydrofuran are particularly preferred.
The base used for this reaction maybe an organic amine, an alkoxide, an alkali metal hydroxide, an alkaline earth metal hydroxide, an alkali metal hydride, an alkaline earth metal hydride or a carbonic acid salt. Suitable examples of the base are 1,8-bis(N,N-dimethylamino)naphthalene, sodium methoxide, sodium ethoxide, sodium phenoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium hydride, potassium hydride, calcium hydride, sodium carbonate, potassium carbonate, sodium hydrogencarbonate, potassium hydrogencarbonate, calcium carbonate and basic alumina. Metal hydrides are particularly preferred. The amount of the base is preferably at least equivalent to the amount of the haloformic acid ester used.
The finished reaction mixture is, concentrated, after filtration if the system contains any solid, to yield a compound (3).
Then, the compound (3) thus obtained is hydrolyzed in an appropriate solvent under alkaline conditions to yield paroxetine. The reaction temperature is preferably from 10 to 150xc2x0 C., more preferably from 20 to 120xc2x0 C.
In the hydrolysis, any solvent resistant to the hydrolytic conditions may be used. Suitable examples of the solvent are diethyl ether, t-butyl methyl ether, tetrahydrofuran, 1,4-dioxane, 1,2-dimethoxyethane, benzene, toluene, xylene, hexane, heptane, petroleum ether, methanol, ethanol, isopropanol, t-butanol, methyl cellosolve, ethyl cellosolve, water and mixtures of at least two of them.
The alkali which provides the alkaline conditions for the hydrolysis may be an alkoxide, an alkali metal hydroxide, an alkaline earth metal hydroxide or a carbonic acid salt. Suitable examples of the alkali are sodium methoxide, sodium ethoxide, sodium hydroxide, potassium hydroxide, calcium hydroxide, magnesium hydroxide, sodium carbonate, potassium carbonate, sodium hydrogencarbonate and calcium carbonate. Among them, metal hydroxides such as alkali metal hydroxides and alkaline earth metal hydroxides are particularly preferred. The alkali may be used in a catalytic amount in relation to the compound (3), but is preferably used in an amount at least equivalent to the compound (3).
From the finished reaction mixture, paroxetine can be obtained by extraction with an appropriate solvent such as toluene.
The compounds represented by the general formula (3) according to the present invention are novel compounds, and among them, those wherein R2 is a lower alkyl group, especially a methyl group or an ethyl, group are especially useful.